C–N
cross-coupling is one of the most valuable and widespread
transformations in organic synthesis. Largely dominated by Pd- and
Cu-based catalytic systems, it has proven to be a staple transformation
for those in both academia and industry. The current study presents
the development and mechanistic understanding of an electrochemically
driven, Ni-catalyzed method for achieving this reaction of high strategic
importance. Through a series of electrochemical, computational, kinetic,
and empirical experiments, the key mechanistic features of this reaction
have been unraveled, leading to a second generation set of conditions
that is applicable to a broad range of aryl halides and amine nucleophiles
including complex examples on oligopeptides, medicinally relevant
heterocycles, natural products, and sugars. Full disclosure of the
current limitations and procedures for both batch and flow scale-ups
(100 g) are also described.
It goes both ways: A thiol-reactive cross-linker based on a bridged azobenzene derivative permits photoreversible control of peptide conformation on irradiation with violet (407 nm) and green (500-550 nm) light (see picture) through isomerization of the cross-linker. The large separation of the absorbance bands of the cis (yellow) and trans (red) isomers enables complete bidirectional photoswitching.
Using an alanine-scanning method, we have found that the antibacterial and hemolytic activities of the amphipathic cyclic decapeptide antibiotic tyrocidine A depend on different structural components. Single substitution of glutamine-6 of the natural product with a cationic amino acid results in a therapeutic index enhancement of up to 140-fold. Successful dissociation of the two intimately associated properties should enable discovery of novel analogues with both high bacterial selectivity and antibacterial potency to counter microbial resistance.
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